Objective
This study is being conducted to evaluate if treatment with tonabersat (Xiflam) has a short-term effect on central retinal thickness in eyes with good vision and DME, or abnormal swelling of the central retina. If there is a beneficial effect on abnormal retinal thickening, then this study will provide critical information for the merit and design of a larger randomized clinical trial.
Background Rationale
At present, at least 5 million people over the age of 40 in the United States are estimated to have DR in the absence of DME, and an additional 800,000 have DME, according to data from the Centers for Disease Control and Prevention. Current therapies involving eye injections and laser techniques are invasive and potentially destructive, and approximately 50% of patients with DME may not respond fully to these standard treatments. Tonabersat (Xiflam), is an oral medication that in prior studies for treatment of migraines was well tolerated with no significant issues. Data from animal models and preclinical studies suggest that tonabersat is likely to have a beneficial effect on DR and DME through blocking inflammatory pathways that contribute to the development and worsening of these retinal abnormalities. Blocking inflammation systemically may also improve other diabetes complications like kidney disease. Given the visit burden, costs and potential adverse events associated with current treatments, a novel well-tolerated, safe, and effective oral medication would have a substantial positive public health impact.
Description of Project
The number of adults living with type 1 diabetes mellitus today is higher than ever, likewise are the rates of associated microvascular complications such as diabetic retinopathy (DR). DR develops and progresses in a large majority of patients with diabetes. Despite recent advances in treatment, DR remains a leading cause of vision loss and new onset blindness in the United States and other developing countries worldwide. Diabetic macular edema (DME), a common consequence of DR, is the most frequent condition that contributes to vision loss in persons with diabetes. Nearly half of all people with DR will develop DME. In eyes with DME, swelling of the central retina results from abnormal leakage from damaged blood vessels from diabetes. When swelling affects the center of the macula, it can reduce vision. This is because the center of the macula is used for sharp vision like reading, driving, and recognizing faces. When vision is already reduced from DME, injections of drugs such as anti-vascular endothelial growth factor (anti-VEGF) and steroid are commonly given in the eye. These injections have been shown to improve the leakage from blood vessels and reduce edema. However, this therapy is not without its disadvantages and risks, such as infection, as well as discomfort, cost and inconvenience associated with frequent treatments. Furthermore, not all eyes treated with anti-VEGF respond successfully with complete resolution of retinal thickening and restoration of vision. Thus, there is an ongoing need for new therapies that are both safe and effective. The purpose of this study is to determine if an oral medication called tonabersat (Xiflam), a medication previously developed and tested in clinical studies for the treatment of migraine, can improve DME over the short term in eyes with good vision. Tonabersat was safe and well-tolerated in previous clinical studies. It acts by blocking connexin43 (Cx43) hemichannels, which are protein structures in cell membranes that allow the movement of molecules. These channels are involved in increasing inflammation pathways that are known to be active in diabetes and retinal diseases such as DME. If tonabersat is effective in improving DME, invasive injections of anti-VEGF or steroid may be avoided or delayed, and treatment burden, such as frequent visits and costs, may be reduced. Thus, this study could provide a major public health contribution if this non-invasive oral treatment is effective in treating DME and can be implemented into clinical care for patients with diabetic eye disease.
Anticipated Outcome
This DRCR Retina Network-sponsored study will evaluate the short-term effects of an oral medication in eyes with abnormal thickening of the central retina and good vision. The DRCR Retina Network has a highly successful track record over the last 19 years in enrolling and completing high-quality, multi-center clinical trials, many of which have been instrumental in setting the current standards of care for diabetic eye disease. As such, we anticipate this study will be similarly enrolled and conducted efficiently and effectively with excellent study participant retention through the 6 months of scheduled follow-up. Given tonabersat’s favorable safety profile in previous studies enrolling approximately 1,000 study participants, we anticipate that this treatment will be well-tolerated. We likewise expect that this rigorously designed study will effectively gather preliminary data to evaluate this novel treatment for DME. Positive results from this Phase 2 study would justify a larger, randomized clinical trial to test the efficacy and long-term effects of tonabersat for vision-threatening diabetic eye disease.
Relevance to T1D
Over 90% of individuals with type 1 diabetes will develop retinal pathology after living 10 or more years with this chronic disease. Patients with type 1 diabetes are at steadily increasing risks of developing advanced diabetic eye complications such as DME, or abnormal swelling of the central retina, the longer their duration of diabetes. DME is most common among the conditions that contribute to vision loss in persons with diabetes with nearly half of all people with DR developing DME. Although therapies are available, these are either potentially destructive or invasive, not to mention requiring frequent and often costly visits. The goal of this study is to evaluate whether a new oral medication is effective at reducing DME and thereby potentially reducing rates of long-term vision loss in patients with type 1 diabetes. Since diabetic retinal abnormalities are the most common cause of vision loss in patients with type 1 diabetes, we anticipate that the results of this study will be highly relevant to all individuals with type 1 diabetes.